Silent information regulator 1 ameliorates oxidative stress injury via PGC-1α/PPARγ-Nrf2 pathway after ischemic stroke in rat.

OBJECTIVE

Astrocytes mediate brain defense against oxidative stress-induced injury. Silent information regulator 1 (SIRT1) has anti-oxidative stress effects in many diseases and is highly expressed in astrocytes. However, the neuroprotective effects of SIRT1 on astrocytes after cerebral ischemia/reperfusion injury are unclear. Therein, we aim to investigate the protective effect of SIRT1 on oxidative stress injury after ischemic stroke and possible mechanisms.

METHODS

We evaluated the effects of SIRT1 in astrocytes after cerebral ischemia/reperfusion injury using oxygen-glucose deprivation/recovery (OGD/R) in astrocytes in vitro and middle cerebral artery occlusion in rats in vivo. siRNA was injected intracerebroventricularly 24 h before Middle cerebral artery (MCA) occlusion (MCAO)/reperfusion(R) to silence SIRT1.

RESULTS

SIRT1 knockdown reduced cell viability, increased oxidative stress, and decreased PGC-1α, PPARγ, Nrf2, heme oxygenase (HO)-1, and NAD(P)H: oxidoreductase-1 (NQO1) expression. Moreover, SIRT1 knockdown also suppressed PGC-1α activity, the PGC-1α/PPARγ interaction, and the PPARγ/PPRE interaction. Similarly, in our in vivo experiments, SIRT1 overexpression and PGC-1α or PPARγ knockdown reduced PGC-1α, PPARγ, Nrf2, HO-1, and NQO1 protein expression and blocked the PGC-1α/PPARγ interaction. SIRT1 overexpression plus PPARγ knockdown inhibited the interaction of PPARγ with PPRE. Nrf2 knockdown blocked Nrf2 expression and downstream proteins induced by SIRT1 overexpression.

CONCLUSION

Overall, our data indicated that SIRT1 directly mediated the PGC-1α/PPARγ pathway in response to focal cerebral ischemia/reperfusion-induced neurological deficit, providing insights into the treatment of focal cerebral ischemia/reperfusion injury.